PML protein organizes heterochromatin domains where it regulates histone H3.3 deposition by ATRX/DAXX

Delbarre, Erwan; Ivanauskiene, Kristina; Spirkoski, Jane; Shah, Akshay; Vekterud, Kristin; Moskaug, Jan Øivind; Bøe, Stig Ove; Wong, Lee H.; Küntziger, Thomas; Collas, Philippe

doi:10.1101/gr.215830.116

Cited by 60 publications

(85 citation statements)

References 54 publications

(76 reference statements)

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“…Owing to their insolubility, PMLs immunoprecipitated using the traditional IP method are predominantly not localized to NBs (Delbarre et al, 2017). We applied a modified immuno‐TRAP technique to overcome the issue and systematically analyze the PML NB‐associated genes or the PML NB‐dictated gene signature (Ching et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…ATRX and DAXX are residents of PML NBs, which have been identified as H3.3 histone chaperones (Lewis, Elsaesser, Noh, Stadler, & Allis, 2010). Recent studies reveal that the PML‐ATRX/DAXX complex associates with chromatin and regulates H3.3 deposition to modulate epigenetics, heterochromatin domain, and DNA replication (Delbarre et al, 2017; Lallemand‐Breitenbach & de The, 2018; Shastrula et al, 2019). Since the loss of heterochromatin, disorganized epigenetics, and abnormal DNA replication are well‐known features of HGPS, we reason that thread‐like PML NBs may perturb the regular function of PML‐ATRX/DAXX complex, thereby contributing to HGPS deficiency.…”

Section: Discussionmentioning

confidence: 99%

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PML2‐mediated thread‐like nuclear bodies mark late senescence in Hutchinson–Gilford progeria syndrome

Wang

Qian

et al. 2020

Aging Cell

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Progerin accumulation disrupts nuclear lamina integrity and causes nuclear structure abnormalities, leading to premature aging, that is, Hutchinson–Gilford progeria syndrome (HGPS). The roles of nuclear subcompartments, such as PML nuclear bodies (PML NBs), in HGPS pathogenesis, are unclear. Here, we show that classical dot‐like PML NBs are reorganized into thread‐like structures in HGPS patient fibroblasts and their presence is associated with late stage of senescence. By co‐immunoprecipitation analysis, we show that farnesylated Progerin interacts with human PML2, which accounts for the formation of thread‐like PML NBs. Specifically, human PML2 but not PML1 overexpression in HGPS cells promotes PML thread development and accelerates senescence. Further immunofluorescence microscopy, immuno‐TRAP, and deep sequencing data suggest that these irregular PML NBs might promote senescence by perturbing NB‐associated DNA repair and gene expression in HGPS cells. These data identify irregular structures of PML NBs in senescent HGPS cells and support that the thread‐like PML NBs might be a novel, morphological, and functional biomarker of late senescence.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

PML2‐mediated thread‐like nuclear bodies mark late senescence in Hutchinson–Gilford progeria syndrome

Wang

Qian

et al. 2020

Aging Cell

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“…In OIS, expression of the oncogene H-RasV12 induces DAXX-dependent relocalization of neo-synthesized H3.3 in the PML-NBs before a drastic reorganization of the chromatin to form senescence-associated heterochromatin foci [35,36]. Hence, the implication of the PML-NBs in the deposition of H3.3 on specific cellular chromatin loci has also been reported [36,37]. The present study shows that the absence of Pml in HSV-1wt latently infected Pml KO mice, or the depletion of PML by shRNA in BJ cells infected with in 1374, significantly affects the co-localization of DAXX and ATRX, but not HIRA and UBN1, with latent/quiescent HSV-1 genomes, confirming previous studies for DAXX/ATRX [38].…”

Section: Discussionmentioning

confidence: 99%

“…The HIRA complex does not normally accumulate in PML-NBs except upon entry of the cell into senescence [33,34]. The histone variant H3.3 itself localizes in PML-NBs in proliferating and senescent cells, linking PML-NBs with the chromatin assembly pathway independently of replication [35–37]. Because vDCP-NBs contain DAXX and ATRX [15,16,38], their involvement in the chromatinization of incoming HSV-1 genomes and/or long-term maintenance of chromatinized HSV-1 genomes is thus plausible.…”

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confidence: 99%

Promyelocytic Leukemia (PML) Nuclear Bodies (NBs) Induce Latent/Quiescent HSV-1 Genomes Chromatinization Through a PML-NB/Histone H3.3/H3.3 Chaperone Axis

Cohen

Corpet

Maroui

et al. 2017

Preprint

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Herpes simplex virus 1 (HSV-1) latency establishment is tightly controlled by promyelocytic leukemia (PML) nuclear bodies (NBs) (or ND10), although their exact implication is still elusive. A hallmark of HSV-1 latency is the interaction between latent viral genomes and PML-NBs, leading to the formation of viral DNA-containing PML-NBs (vDCP-NBs). Using a replication-defective HSV-1-infected human primary fibroblast model reproducing the formation of vDCP-NBs, combined with an immuno-FISH approach developed to detect latent/quiescent HSV-1, we show that vDCP-NBs contain both histone H3.3 and its chaperone complexes, i.e., DAXX/ATRX and HIRA complex (HIRA, UBN1, CABIN1, and ASF1a). HIRA also co-localizes with vDCP-NBs present in trigeminal ganglia (TG) neurons from HSV-1-infected wild type mice. ChIP-qPCR performed on fibroblasts stably expressing tagged H3.3 (e-H3.3) or H3.1 (e-H3.1) show that latent/quiescent viral genomes are chromatinized almost exclusively with e-H3.3, consistent with an interaction of the H3.3 chaperones with multiple viral loci. Depletion by shRNA of single proteins from the H3.3 chaperone complexes only mildly affects H3.3 deposition on the latent viral genome, suggesting a compensation mechanism. In contrast, depletion (by shRNA) or absence of PML (in mouse embryonic fibroblast (MEF) pml−/- cells) significantly impacts the chromatinization of the latent/quiescent viral genomes with H3.3 without any overall replacement with H3.1. Consequently, the study demonstrates a specific epigenetic regulation of latent/quiescent HSV-1 through an H3.3-dependent HSV-1 chromatinization involving the two H3.3 chaperones DAXX/ATRX and HIRA complexes. Additionally, the study reveals that PML-NBs are major actors in latent/quiescent HSV-1 H3.3 chromatinization through a PML-NB/histone H3.3/H3.3 chaperone axis.Author summaryAn understanding of the molecular mechanisms contributing to the persistence of a virus in its host is essential to be able to control viral reactivation and its associated diseases. Herpes simplex virus 1 (HSV-1) is a human pathogen that remains latent in the PNS and CNS of the infected host. However, the latency is unstable, and frequent reactivations of the virus are responsible for PNS and CNS pathologies. It is thus crucial to understand the physiological, immunological and molecular levels of interplay between latent HSV-1 and the host. Promyelocytic leukemia (PML) nuclear bodies (NBs) play a major role in controlling viral infections by preventing the onset of lytic infection. In previous studies, we showed a major role of PML-NBs in favoring the establishment of a latent state for HSV-1. A hallmark of HSV-1 latency establishment is the formation of PML-NBs containing the viral genome, which we called “viral DNA-containing PML-NBs” (vDCP-NBs). The genome entrapped in the vDCP-NBs is transcriptionally silenced. This naturally occurring latent/quiescent state could, however, be transcriptionally reactivated. Therefore, understanding the role of PML-NBs in controlling the establishment of HSV-1 latency and its reactivation is essential to design new therapeutic approaches based on the prevention of viral reactivation.

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“…3C). Furthermore, pPK999 contains the Egfr gene, 154 for which transcript levels are higher in MEFs (FPKM value 51.5) (Delbarre et al 2017) 155 compared to mESCs (FPKM value 0.2 (Supplemental Table 1)). This is an example of a genomic 156 locus that is nucleolar-associated and transcriptionally repressed in mESCs, and which is no 157 longer associated and becomes more active in MEFs.…”

Section: Introduction 44mentioning

confidence: 99%

Distinct features of nucleolus-associated domains in mouse embryonic stem cells

Bizhanova

Yan

et al. 2019

Preprint

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24Background: Heterochromatin in eukaryotic interphase cells frequently localizes to the nucleolar 25 periphery (nucleolus-associated domains, NADs) and the nuclear lamina (lamina-associated 26 domains, LADs). Gene expression in somatic cell NADs is generally low, but NADs have not 27 been characterized in mammalian stem cells. 28Results: Here, we generated the first genome-wide map of NADs in mouse embryonic stem cells 29 (mESCs) via deep sequencing of chromatin associated with biochemically-purified nucleoli. 30As we had observed in mouse embryonic fibroblasts (MEFs), the large Type I subset of NADs 31 overlaps with constitutive LADs and is enriched for features of constitutive heterochromatin, 32including late replication timing and low gene density and expression levels. Conversely, the 33 Type II NAD subset overlaps with loci that are not lamina-associated, but in mESCs, Type II 34NADs are much less abundant than in MEFs. mESC NADs are also much less enriched in 35H3K27me3 modified regions than are NADs in MEFs. Additionally, comparision of MEF and 36 mESC NADs revealed enrichment of developmentally regulated genes in cell type-specific 37NADs. Together, these data indicate that NADs are a developmentally dynamic component of 38 heterochromatin. 39Conclusions: These studies implicate association with the nucleolar periphery as a mechanism 40 for developmentally-regulated gene silencing, and will facilitate future studies of NADs during 41 mESC differentiation. 42 43 3 are accompanied by spatial separation: heterochromatin is mainly found at the nuclear periphery 47 and nucleolar periphery, where they comprise nucleolus-associated domains (NADs) (Németh et 48 al. 2010; van Koningsbruggen et al. 2010) and lamina-associated domains (LADs) (Pickersgill et 49 al. 2006;Guelen et al. 2008;Peric-Hupkes et al. 2010), respectively. Studies in multiple 50 organisms indicate that sequestration of heterochromatin to the nuclear and nucleolar peripheries 51

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PML protein organizes heterochromatin domains where it regulates histone H3.3 deposition by ATRX/DAXX

Cited by 60 publications

References 54 publications

PML2‐mediated thread‐like nuclear bodies mark late senescence in Hutchinson–Gilford progeria syndrome

PML2‐mediated thread‐like nuclear bodies mark late senescence in Hutchinson–Gilford progeria syndrome

Promyelocytic Leukemia (PML) Nuclear Bodies (NBs) Induce Latent/Quiescent HSV-1 Genomes Chromatinization Through a PML-NB/Histone H3.3/H3.3 Chaperone Axis

Distinct features of nucleolus-associated domains in mouse embryonic stem cells

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